In this new R01, we will capitalize on the unique resources of our Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) program, a molecular environmental epidemiology birth cohort study that won the 1999 NIEHS Progress and Achievement Award, to conduct a rigorous study of the potential impact of population-wide levels of exposure to fluoride on neurodevelopment. This effort addresses a 2007 US National Research Council report which concluded that more research is needed to address the possibility that population-wide levels of fluoride exposure may pose a significant threat to neurobehavior. The exceptional data and resources of ELEMENT has allowed our team to publish over 40 papers related to the impact of prenatal and childhood exposure to lead and other toxicants on neurobehavioral and physical development. Using levels of fluoride measured in our archived urine, fasting plasma and toenail specimens, validated measures widely recognized as being the best available biomarkers of fluoride exposure, we propose to study the impact of prenatal and childhood fluoride exposures on widely used and validated measures of neurobehavior at 2 to 14 years of age utilizing 3 of the 4 cohorts of ELEMENT. Our pilot research on archived urine and plasma samples from 40 randomly chosen mother-offspring pairs using rigorous and cross-validated laboratory methods indicates that our ELEMENT subjects have a distribution of fluoride levels that will enable us to pursue our specific aims. Further, our pilot data shows evidence of an inverse relationship between prenatal biomarkers of fluoride exposure and general cognitive function at 2 years (Bayley Scales of Mental Development), 4 years (McCarthy Scales of Children's Abilities) and 7-14 years (Wechsler Abbreviated Scales of Intelligence). Our overall goals will be to conduct a full investigation to () address hypotheses on the potential impact of pre- and postnatal exposures to fluoride on measures of overall neurobehavioral function; (B) explore the potential impacts of fluoride exposure on specific domains of neurobehavioral function, the shape of the dose-response relationships, differential susceptibility in relation to time windows of exposure (prenatal v. childhood), and, using archived data, potential interactions with lead exposure, another widely- distributed neurotoxicant; and (C) conduct a study of offspring to examine the drinking water, dietary, dentifrice, lifestyle, and other determinants of current urinary and toenail fluoride leves. Given the power of our archived resources and sample sizes, we will be able to accomplish this research at a small fraction of the cost and time required of a new study. PUBLIC HEALTH RELEVANCE: This research will directly address the issue as to whether population-wide levels of prenatal and/or childhood fluoride exposure is a significant risk factor for some forms of adverse neurobehavioral performance. Given the widespread nature of fluoride use and exposure and the lack of rigorous epidemiologic research on this topic of the current base of evidence, this research promises to make a major contribution to fluoride risk assessment and policy decision-making.